A novel locus for split-hand/foot malformation associated with tibial hemimelia (SHFLD syndrome) maps to chromosome region 17p13.1–17p13.3

Abstract

Split-hand/foot malformation (SHFM) associated with aplasia of long bones, SHFLD syndrome or Tibial hemimelia-ectrodactyly syndrome is a rare condition with autosomal dominant inheritance, reduced penetrance and an incidence estimated to be about 1 in 1,000,000 liveborns. To date, three chromosomal regions have been reported as strong candidates for harboring SHFLD syndrome genes: 1q42.2-q43, 6q14.1 and 2q14.2. We characterized the phenotype of nine affected individuals from a large family with the aim of mapping the causative gene. Among the nine affected patients, four had only SHFM of the hands and no tibial defects, three had both defects and two had only unilateral tibial hemimelia. In keeping with previous publications of this and other families, there was clear evidence of both variable expression and incomplete penetrance, the latter bearing hallmarks of anticipation. Segregation analysis and multipoint Lod scores calculations (maximum Lod score of 5.03 using the LINKMAP software) using all potentially informative family members, both affected and unaffected, identified the chromosomal region 17p13.1-17p13.3 as the best and only candidate for harboring a novel mutated gene responsible for the syndrome in this family. The candidate gene CRK located within this region was sequenced but no pathogenic mutation was detected.

17p13.3 microduplications are associated with split-hand/foot malformation and long-bone deficiency (SHFLD)

“…11,12 SHFLD3 was mapped in a Brazilian family to an 861 kb interval at 17p13.1-17p13.3. 13 In this study we report three independent and overlapping microduplications at 17p13.3 in individuals with SHFLD. The first, a 254 kb duplication, segregates with the disorder in a three-generation family and manifests with variable expressivity and incomplete penetrance.…”

“…The third, a 430 kb duplication versus triplication, segregates with SHFLD in three affected members of a multi-generational family. These duplications share a 173 kb region of overlap and are located within the SHFLD3 region described by Lezirovitz et al 13 …”

Clinical, genetic, and molecular aspects of split‐hand/foot malformation: An update

“…This locus was mapped by linkage analysis in a family with autosomal dominant SHFLD [Lezirovitz et al, 2008]. Overlapping 17p13.3 microduplications ranging from 254 to 527 kb were subsequently identified by array CGH and shown to segregate with the limb phenotype in three unrelated families with SHFLD, and penetrance was incomplete [Armour et al, 2011].…”

Duplications ofBHLHA9are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion

“…In a pedigree suggestive of X-linked inheritance (family 10, figure 1A and supplementary figure 2), we identified a duplication of 180 kb on chromosome 17p13.3 (figure 1A). We further analysed a large Brazilian family previously mapped to the same region14 and identified a 110 kb microduplication (family 16, figure 1A). To identify further families and to test the frequency of 17p13 duplications, we screened a cohort of another 54 families with non-syndromic SHFM including another 11 cases with long bone deficiency (SHFLD).…”